rs7315124

Variant names:

• chr12-5991805-G-A
• rs7315124
• NM_000552.5:c.6798+14C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.6798+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,308 control chromosomes in the GnomAD database, including 544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (198 hom., cov: 33)
  • Exomes 𝑓: 0.013 (346 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.173
• Publications: 3 publications found

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

VWF Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-5991805-G-A is Benign according to our data. Variant chr12-5991805-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0869 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.6798+14C>T		intron	N/A	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.6798+14C>T		intron	N/A	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4928 AN: 152172 Hom.: 197 Cov.: 33

Gnomad AFR AF: 0.0893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00820

Gnomad OTH AF: 0.0283

GnomAD2 exomes AF: 0.0187 AC: 4694 AN: 251040 AF XY: 0.0193

Gnomad AFR exome AF: 0.0880

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00830

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0127 AC: 18579 AN: 1461018 Hom.: 346 Cov.: 32 AF XY: 0.0138 AC XY: 10031 AN XY: 726852

African (AFR) AF: 0.0933 AC: 3121 AN: 33452

American (AMR) AF: 0.0138 AC: 615 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 635 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0482 AC: 4155 AN: 86210

European-Finnish (FIN) AF: 0.00127 AC: 68 AN: 53356

Middle Eastern (MID) AF: 0.0292 AC: 154 AN: 5274

European-Non Finnish (NFE) AF: 0.00791 AC: 8795 AN: 1111852

Other (OTH) AF: 0.0172 AC: 1035 AN: 60326

GnomAD4 genome AF: 0.0324 AC: 4936 AN: 152290 Hom.: 198 Cov.: 33 AF XY: 0.0318 AC XY: 2369 AN XY: 74480

African (AFR) AF: 0.0893 AC: 3709 AN: 41542

American (AMR) AF: 0.0193 AC: 295 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0424 AC: 204 AN: 4814

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00820 AC: 558 AN: 68030

Other (OTH) AF: 0.0275 AC: 58 AN: 2110

Alfa AF: 0.0226 Hom.: 21

Bravo AF: 0.0353

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary von Willebrand disease (1)
-	-	1	not provided (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 2 (1)
-	-	1	von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.21
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7315124; hg19: chr12-6100971;